Methods of synthesizing cinacalcet and salts thereof

ABSTRACT

Methods of preparing cinacalcet, cinacalcet derivatives, and salts thereof is disclosed herein. Also disclosed herein are polymorphs of cinacalcet, compositions of cinacalcet, and methods of treating a subject by administering cinacalcet, wherein cinacalcet is prepared by the disclosed methods.

FIELD OF THE INVENTION

The present disclosure is directed to synthetic processes andintermediates of the calcimimetic agent cinacalcet and salts thereof,polymorphs of cinacalcet, compositions of the same, and methods oftreating subject suffering from hypercalcemia using the compositions.

BACKGROUND OF THE INVENTION

Sensipar® (cinacalcet) is a calcimimetic agent that has the chemicalnameN-[1-(R)-(−)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropanehydrochloride, has the empirical formula C₂₂H₂₂F₃N·HCl, and has thestructural formula

The molecular weight of the hydrochloride salt is 393.9 g/mol and thefree base is 357.4 g/mol. There is one chiral center in the molecule(marked with a *), and the R enantiomer is the more potent enantiomer.

Cinacalcet hydrochloride is commercially available as Sensipar® andMimpara®. The calcimimetic agent is used to increase the sensitivity ofthe calcium-sensing receptor to activation by extracellular calcium.This calcimimetic has been shown to be therapeutically effective in thetreatment of patients with chronic kidney disease on dialysis who havesecondary hyperparathyroidism and of hypercalcemia in patients withparathyroid carcinoma. Today there are more than 300,000 kidney dialysispatients with chronic kidney disease (CKD) in the U.S. alone. Nearly allof these patients suffer from secondary hyperparathyroidism (HPT), whichis a progressive disease, associated with increases in parathyroidhormone (PTH) levels and abnormal calcium and phosphorus metabolism. Ina typical patient having mild HPT, the serum intact parathyroid hormone(iPTH) levels are 300 to 500 pg/ml; a patient having moderate HPT has aniPTH of 500 to 800 pg/ml; and a patient with severe HPT has an iPTH ofgreater than 800 pg/ml. A normal iPTH level should be in the range ofabout 250 pg/ml. The lower limit of normal calcium level in humans isabout 8.4 mg/dL. HPT can develop early during the course of CKD andcontinues to progress as kidney function declines. Untreated secondaryHPT is characterized by abnormal calcium and phosphorus levels and isassociated with serious consequences, including cardiovascularmorbidity.

Increased PTH stimulates osteoclastic activity resulting in corticalbone resorption and marrow fibrosis. Sensipar® is the first treatmentthat meets a significant medical need in patients with secondary HPT tolower the levels of PTH, calcium, and phosphorus in the blood, in orderto prevent progressive bone disease and the systemic consequences ofdisordered mineral metabolism. Reduction of PTH levels in CKD patientson dialysis with uncontrolled secondary HPT has been shown to havepositive effects on bone-specific alkaline phosphatase (BALP), boneturnover and bone fibrosis.

PTH secretion is regulated through the action of a calcium-sensingreceptor on the cell surface of the parathyroid gland. Sensipar®directly lowers PTH levels by increasing the sensitivity of thiscalcium-sensing receptor to extracellular calcium. The reduction in PTHis associated with a concomitant decrease in serum calcium levels.

Sensipar® allows practitioners to reduce PTH while loweringcalcium-phosphorus product, which is consistent with the National KidneyFoundation's Kidney Disease Outcomes Quality Initiative (K/DOQI)clinical practice guidelines for bone metabolism and disease in chronickidney disease. Prior to its development, the only available medicaltreatments for patients with secondary HPT were phosphate binders andvitamin D sterols, which may elevate calcium and/or phosphorus levels.Such elevation would frequently require treatment to be interrupted andlead to an inadequate control of PTH.

It is now well-accepted that Sensipar® provides an excellent targetedtreatment of secondary HPT with its unique mechanism of action that actsdirectly on the calcium-sensing receptor. Sensipar® provides significantimprovement over traditional therapy to provide an important new tool tohelp dialysis patients suffering from secondary HPT. It also issuccessful in lowering calcium levels in patients with hypercalcemia dueto parathyroid carcinoma. Patients with parathyroid carcinoma have arare, serious cancer of the parathyroid gland results in excesssecretion of PTH. Thus, parathyroid carcinoma is one form of primaryHPT. The disease is complicated by elevated calcium levels in the blood.High calcium levels can lead to anxiety, depression, nausea, vomiting,bone fractures, kidney stones and in some cases coma. Surgical removalof the parathyroid gland is the only curative therapy for this diseasebut is not successful in all cases. Sensipar® was shown to reduce highlevels of calcium in patients with parathyroid carcinoma.

A need exists for synthetic processes for cinacalcet, cinacalcetderivatives, and salts thereof.

The present disclosure is directed to processes and intermediates forthe synthesis of cinacalcet, cinacalcet derivatives, and salts thereof.In various embodiments, a cinacalcet salt is prepared. In a specificclass of embodiments, cinacalcet hydrochloride is prepared.

Thus, one aspect of the invention provides a method of preparingcinacalcet using allylic amination. The method comprises (a) admixing acompound of formula (I) and a compound of formula (II) under conditionsthat permit cross-metathesis to produce a compound of formula (III):

wherein each R¹ is the same or different and is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, OC₁-C₆ alkyl, aryl, O-aryl,heteroaryl, and O-heteroaryl; b) admixing compound (III) and1-(1-naphthyl)ethylamine or a salt thereof under conditions to permitallylic amination to produce a compound of formula (IV)

and c) reducing compound (IV) under conditions that permit reduction toproduce cinacalcet or a salt thereof. In various embodiments, theconditions that permit cross-metathesis can include performing saidcross-metathesis in the presence of a Ru or Mo catalyst. In variousembodiments, the conditions that permit allylic amination can includeperforming said allylic amination in the presence of a Pd, Ru, Ir, Rh,Pt, or Ni catalyst. In various embodiments, the conditions that permitreduction can include performing said reduction in the presence of areducing agent (e.g., hydrogen, hydride, or the like) and a Pd, Ni, Pt,Rh, Ir, or Ru catalyst.

In another aspect, a method of preparing cinacalcet or salt thereofcomprises a) admixing a compound of formula (V) and1-(1-naphthyl)ethylamine under conditions to permit allylic amination toproduce a compound of formulation (IV):

wherein R² is selected from the group consisting of hydrogen,C₁-C₆alkyl, aryl, heteroaryl, C(O)C₁-C₆ alkyl, C(O)aryl, C(O)heteroaryl,and C(O)OC₁-C₆ alkyl; and b) reducing compound (IV) under conditionsthat permit reduction to produce cinacalcet or a salt thereof. Invarious embodiments, the conditions that permit allylic amination caninclude performing said allylic amination in the presence of a Pdcatalyst. In various embodiments, the conditions that permit reductioncan include performing said reduction in the presence of a reducingagent (e.g., hydrogen, hydride, or the like) and a Pd, Ni, Pt, Rh, Ru,or Ir catalyst. In various embodiments, the compound of formula (V) canbe prepared via a method comprising admixing3-trifluoromethyl-benzaldehyde and a vinyl reagent to form a compound offormula (V). In specific embodiments, the vinyl reagent is vinyllithium, vinyl borate, vinyl boronate, vinyl zinc halide, divinyl zinc,or vinyl magnesium halide.

In another aspect, a method of preparing cinacalcet or salt thereofcomprises a) admixing a compound of formula (V), where R² is hydrogen,and 1-(1-naphthyl)ethyl isocyanate under conditions that permit theformation of a compound of formula (VI):

admixing compound (VI) and a catalyst under conditions that permit C—Oto C—N rearrangement to form a compound of formula (IV)

and c) reducing compound (IV) under conditions that permit reduction toproduce cinacalcet or a salt thereof. In various embodiments, theconditions which permit C—O to C—N rearrangement can include performingsaid C—O to C—N rearrangement in the presence of a metal catalyst,wherein the metal catalyst is selected from the group consisting of Pd,Ru, Ni, Ir, Rh, Hg, Au, and Pt. In various embodiments, the conditionsthat permit reduction can include performing said reduction in thepresence of a reducing agent (e.g., hydrogen, hydride, or the like) anda Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst.

In another aspect, a method of preparing cinacalcet or salt thereofcomprises a) admixing 3-trifluoromethyl-cinnamic acid and1-(1-naphthyl)ethylamine under conditions to permit amide bond formationto form a compound of formula (VIIB)

and b) reducing compound (VIIB) under conditions that permit reductionto form cinacalcet or a salt thereof. In various embodiments, theconditions that permit amide bond formation can include performing saidamide bond formation in the presence of a peptide coupling agent. Inspecific embodiments, the peptide coupling agent can be a chlorinatingagent (e.g., oxalyl chloride, thionyl chloride, or phosphorustrichloride), a mixed anhydride, DIC, DCC, EDCI, CDI, HOBt, HOAt,pentafluorophenol, HBTU, HATU, and Mukaiyama's reagent. In variousembodiments, the conditions that permit reduction can include performingsaid reduction in the presence of a reducing agent (e.g., hydrogen,hydride, or the like) and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst. Invarious embodiments, the reduction can be in the presence of borane orlithium aluminum hydride. In certain embodiments, the reductionconditions are sufficient to reduce both the double bond and the amidebond, while in certain other embodiments, two different reductionconditions are used to reduce the double bond and the amide bond, ineither order.

In still another aspect, a method of preparing cinacalcet or saltthereof comprises a) admixing a compound of formula (VIII) and acompound of formula (IX), under conditions that promote coupling ofcompound (VIII) and compound (IX) to form compound (X)

wherein X is selected from the group consisting of chlorine, bromine,iodine, OSO₂C₆H₄CH₃, OSO₂CH₃, OSO₂CF₃, OSO₂C₄F₉ and N₂ ⁺ and R isselected from the group consisting of hydrogen, benzyl, substitutedbenzyl, BOC, CBZ, and acetate; and b) reducing compound (XI) underconditions that permit reduction to form cinacalcet, a cinacalcetderivative, or a salt thereof. In various embodiments, the conditionsthat promote coupling of compound (VIII) and compound (IX) can includeperforming said coupling in the presence of a Pd or Ni catalyst. Invarious embodiments, the conditions that permit reduction can includeperforming said reduction in the presence of a reducing agent (e.g.,hydrogen, hydride, or the like) and a Pd, Ni, Ir, Pt, Rh, Ru or Ircatalyst. In embodiments where R is not hydrogen, the method optionallyfurther includes deprotecting the cinacalcet derivative to formcinacalcet or a salt thereof.

In yet another aspect, a method of preparing cinacalcet, a derivativethereof, or salt thereof comprises a) admixing a compound of formula(VIII) and a compound of formula (XI), under conditions that promotecoupling of compound (VIII) and compound (XI) to form compound (XII)

wherein X is selected from the group consisting of chlorine, bromine,iodine, OSO₂C₆H₄CH₃, OSO₂CH₃, OSO₂CF₃, OSO₂C₄F₉, and N₂ ⁺ and R isselected from the group consisting of hydrogen, benzyl, BOC, CBZ, andacetate; b) reducing compound (XII) under conditions that permitreduction to form cinacalcet, a cinacalcet derivative, or a saltthereof. In various embodiments, the conditions that promote coupling ofcompound (VIII) and compound (XI) can include performing said couplingin the presence of a Pd catalyst or a Ru catalyst. In variousembodiments, the conditions that permit reduction can include performingsaid reduction in the presence of a reducing agent (e.g., hydrogen,hydride, or the like) and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst. Inembodiments where R is not hydrogen, the method optionally furtherincludes deprotecting the cinacalcet derivative to form cinacalcet or asalt thereof.

In still another aspect, a method of preparing cinacalcet or saltthereof comprises reducing a compound of formula (XIII) under conditionsthat permit reduction to form cinacalcet or a salt thereof

wherein R is selected from the group consisting of hydrogen, benzyl,substituted benzyl, BOC, Cbz, and acetate. In various embodiments, themethod further can include (i) admixing a compound of formula (VIII) andpropiolic acid or an ester thereof under conditions that permit couplingof compound (VIII) and propiolic acid or an ester thereof to form acompound of formula (XIV)

wherein X is selected from the group consisting of chlorine, bromine,iodine, OSO₂C₆H₄CH₃, OSO₂CH₃, OSO₂CF₃, OSO₂C₄F₉, and N₂ ⁺ and R¹ isselected from the group consisting of hydrogen, C₁-C₆ alkyl, and aryl;and (ii) admixing compound (XIV) and 1-(1-naphthyl)ethylamine or a saltthereof under conditions that permit amide bond formation to form thecompound of formula (XIII). In a specific class of embodiments, theconditions that permit coupling of compound (VIII) and propiolic acid oran ester thereof can include performing said coupling in the presence ofa Pd catalyst. In various embodiments, the method further comprisesadmixing a compound of formula (VIII) and a compound of formula (XV)under conditions that permit coupling of a compound of formula (VIII)and a compound of formula (XV) to form the compound of formula (XIII)

wherein X is selected from the group consisting of chlorine, bromine,iodine, OSO₂C₆H₄CH₃, OSO₂CH₃, OSO₂CF₃, OSO₂C₄F₉, and N₂ ⁺. In a specificclass of embodiments, the conditions that permit coupling of thecompound of formula (VIII) and the compound of formula (XV) can includeperforming said coupling in the presence of a Pd catalyst. In variousembodiments, the method includes admixing3-trifluoromethyl-phenylacetylene and 1-(1-naphthyl)ethyl isocyanateunder conditions that permit the coupling of3-trifluoromethyl-phenylacetylene and 1-(1-naphthyl)ethyl isocyanate toform the compound of formula (XIII), wherein R is H. In a specific classof embodiments, the conditions that permit coupling of3-trifluoromethyl-phenylacetylene and 1-(1-naphthyl)ethyl isocyanate caninclude performing said coupling in the presence of a base. Inembodiments where R is not H, the method optionally further includesdeprotecting the cinacalcet derivative to form cinacalcet or a saltthereof.

In another aspect, a method of preparing cinacalcet, a derivativethereof, or salt thereof comprises reducing a compound of formula (XVI)under conditions that permit reduction to form cinacalcet, a cinacalcetderivative, or a salt thereof

wherein R is selected from the group consisting of hydrogen, benzyl,substituted benzyl, BOC, Cbz, and acetate. In various embodiments, themethod further comprises admixing a compound of formula (VIII) and acompound of formula (XVII) under conditions that permit coupling ofcompound (VIII) and compound (XVII) to form compound (XVI),

wherein X is selected from the group consisting of chlorine, bromine,iodine, OSO₂C₆H₄CH₃, OSO₂CH₃, OSO₂CF₃, OSO₂C₄F₉, and N₂ ⁺. In a specificclass of embodiments, the conditions that permit coupling of formula(VIII) and formula (XVII) can include performing said coupling in thepresence of a Pd catalyst. In embodiments where R is not hydrogen, themethod optionally further includes deprotecting the cinacalcetderivative to form cinacalcet or a salt thereof.

In yet another aspect, a method of preparing cinacalcet or salt thereofcomprises a) admixing a compound of formula (I) and a compound offormula (XVIII) under conditions that permit cross-metathesis to producea compound of formula (IV):

wherein each R¹ is the same or different and is selected from the groupconsisting of hydrogen and C₁-C₆ alkyl; and b) reducing compound (IV)under conditions that permit reduction to produce cinacalcet or a saltthereof. In various embodiments, the conditions that permitcross-metathesis can include performing said cross-metathesis in thepresence of a Ru catalyst. In various embodiments, each R¹ is selectedfrom hydrogen and methyl. In various embodiments, the conditions thatpermit reduction in step (b) can include performing said reduction inthe presence of a reducing agent (e.g., hydrogen, hydride, or the like)and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst.

In still another aspect, a method of preparing cinacalcet or saltthereof comprises a) admixing a compound of formula (I) and a compoundof formula (XIX) under conditions that permit cross-metathesis toproduce a compound of formula (VIIB):

wherein each R¹ is the same or different and is selected from the groupconsisting of hydrogen and C₁-C₆ alkyl; and b) reducing compound (VIIB)under conditions that permit reduction to produce cinacalcet or a saltthereof. In various embodiments, the conditions that permitcross-metathesis can include performing said cross-metathesis in thepresence of a Ru catalyst. In various embodiments, each R¹ is selectedfrom hydrogen and methyl. In various embodiments, the conditions thatpermit reduction in step (b) can include performing said reduction inthe presence of a reducing agent (e.g., hydrogen, hydride, or the like)and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst.

In another aspect, a method of preparing cinacalcet or salt thereofcomprises a) admixing 3-(trifluoromethyl)styrene, carbon monoxide, andhydrogen, under conditions that permit hydroformylation to produce3-(3-trifluoromethylphenyl)propanal; b) admixing3-(3-trifluoromethylphenyl)propanal and 1-(1-naphthyl)ethylamine underconditions that permit imine formation to form a compound of formula(XX)

and c) reducing the compound of formula (XX) under conditions thatpermit reduction to produce cinacalcet or a salt thereof. In variousembodiments, the conditions to permit hydroformylation can includeperforming said hydroformylation in the presence of a Rh, Co, or Ptcatalyst. In various embodiments, the conditions that permit imineformation can include performing said imine formation in the presence ofan acid. In various embodiments, the conditions to permit reduction caninclude performing said reduction in the presence of a reducing agent(e.g., hydrogen, hydride, or the like) and a Pd, Ni, Ir, Pt, Rh, Ru orIr catalyst or in the presence of a hydride source, such as lithiumaluminum hydride.

In another aspect, a method of preparing cinacalcet or a salt thereofcomprises a) admixing a compound of formula (VIIIA) and a compound offormula (XIA), under conditions that promote the coupling of compound(VIIIA) and compound (XIA) to form a compound of formula (VII):

wherein X′ is selected from the group consisting of B(OH)₂, Si(OR³)₃,Sn(R³)₃, and Ti(OR³)₃, and R³ is the same or different and isindependently selected from the group consisting of hydrogen andC₁₋₆alkyl; and b) reducing compound (VII) under conditions that permitreduction to form cinacalcet or a salt thereof. In various embodiments,the conditions that promote the coupling of compound (VIIIA) andcompound (XIA) can include performing the coupling in the presence of aRh or Pd catalyst. In various embodiments, the conditions that permitreduction can include performing said reduction in the presence of areducing agent. In a specific class of embodiments, the reducing agentcan comprise sodium borohydride (NaBH₄), lithium borohydride (LiBH₄),calcium borohydride (Ca(BH₄)₂), lithium aluminum hydride (LiAlH₄) orcomplexes of BH₃ with THF, Et₃N or Me₂S.

In still another aspect, a method of preparing cinacalcet or saltthereof comprises admixing 3-(trifluoromethyl)styrene, carbon monoxide,hydrogen and 1-(1-naphthyl)ethylamine, under conditions that permithydroformylation, imine formation, and reduction (hydroaminomethylation)to produce cinacalcet or a salt thereof. In various embodiments, theconditions that permit hydroformylation, imine formation, and reductioncan include performing said hydroformylation, said imine formation, andsaid reduction in the presence of a Rh or Co catalyst.

In yet another aspect, a method of preparing cinacalcet or salt thereofcomprises admixing 1-(3-trifluoromethylphenyl)-2-propene, borane, andN-chloro-1-(1-naphthyl)ethylamine under conditions that permithydroboration and C—N coupling to form cinacalcet or a salt thereof. Invarious embodiments, the conditions to permit reduction can includeperforming said reduction in the presence of a base.

In a specific class of embodiments, the processes disclosed herein canprovide cinacalcet hydrochloride. In various embodiments, the processesdisclosed herein can provide cinacalcet hydrochloride having a powder Xray powder diffraction (XRPD) pattern having peaks at diffraction angle2θ of about 16.6942; 17.6152; 19.4992; 20.2946; and 20.5877. In variousembodiments, the XRPD pattern may further comprise at least onediffraction angle 2θ peak selected from the group consisting of 12.3402;14.4334; 15.3545; 16.443; 18.2013; 18.6618; 19.9178; 21.7599; 21.9692;22.4297; 24.0206; and 25.0672. In various other embodiments, thecrystalline polymorph of the invention has an XRPD pattern comprises atleast diffraction angle 2 θ peaks at about 12.3402; 14.4334; 15.3545;16.443; 16.6942; 17.6152; 18.2013; 18.6618; 19.4992; 19.9178; 20.2946;20.5877; 21.7599; 21.9692; 22.4297; 24.0206; and 25.0672. In still otherembodiments, the crystalline polymorph has an XRPD pattern comprisesdiffraction angle 2 θ peaks at about 12.3402; 14.4334; 15.3545; 16.443;16.6942; 17.6152; 18.2013; 18.6618; 19.4992; 19.9178; 20.2946; 20.5877;21.7599; 21.9692; 22.4297; 24.0206; and 25.0672. In a specificembodiment, the cinacalcet hydrochloride produced via the disclosedmethods is polymorph III.

In another aspect, compositions of cinacalcet hydrochloride prepared viaany of the disclosed methods are disclosed. The compositions can includethe cinacalcet hydrochloride and a pharmaceutically acceptable carrier.

In yet another aspect, methods of treating a subject suffering fromhypercalcemia comprising administering to said subject a composition asdisclosed herein, wherein the composition comprises a therapeuticallyeffective amount of cinacalcet or salt thereof.

DETAILED DESCRIPTION

Disclosed herein are synthetic processes for the preparation ofcinacalcet, cinacalcet derivatives, or salts thereof, collectivelyreferred to as “cinacalcet” throughout this disclosure.

The compounds, intermediates, and polymorphs disclosed herein can be inan isolated or purified form. Such forms include those that are at leastabout 80% pure by weight, as measured by an analytical process, such asone or more of liquid chromatography, elemental analysis, massspectrometry, nuclear magnetic resonance, gas chromatography, and thelike. Other isolated or purified forms can include at least about 85%,at least about 90%, at least about 91%, at least about 92%, at leastabout 93%, at least about 94%, at least about 95%, at least about 96%,at least about 97%, at least about 98%, and at least about 99%.

The various synthetic processes are discussed in detail below.

Allylic Amination Routes

Cinacalcet can be prepared using an allylic amination, via two syntheticpathways. In one pathway, a 3-trifluoromethyl-styrene derivative (acompound of formula (I)) reacts with a 2-butendiol ester derivative (acompound of formula (II)) under cross metathesis conditions to form acompound of formula (III). (See Scheme 1, step (1a)). The intermediatecompound of formula (III) then undergo allylic amination with1-(1-naphthyl)ethylamine to provide a compound of formula (IV) (Scheme1, step (1b)). Compound (IV) can then be reduced under the appropriateconditions to form cinacalcet or a salt thereof (Scheme 1, step (1c)).

For compounds of formulae (I), (II), and (III), R¹ can be independentlyhydrogen, C₁-C₆ alkyl, OC₁-C₆ alkyl, aryl, O-aryl, heteroaryl, orO-heteroaryl. In various embodiments, the compound of formula (III) hasa R¹ of C₁₋₆alkyl when subjected to the conditions of step (1b).

As used herein, the term “alkyl” refers to straight chained and branchedhydrocarbon groups, nonlimiting examples of which include methyl, ethyl,and straight chain and branched propyl and butyl groups.

As used herein, the term “aryl” refers to a monocyclic or polycyclicaromatic group, preferably a monocyclic or bicyclic aromatic group,e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group canbe unsubstituted or substituted with one or more, and in particular oneto four groups independently selected from, for example, halo, alkyl,alkenyl, OCF₃, NO2, CN, NC, OH, alkoxy, amino, CO₂H, CO₂alkyl, aryl, andheteroaryl. Exemplary aryl groups include, but are not limited to,phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl,methoxyphenyl, trifluoromethylphenyl, nitrophenyl,2,4-methoxychlorophenyl, and the like.

As used herein, the term “heteroaryl” refers to a monocyclic or bicyclicring system containing one or two aromatic rings and containing at leastone nitrogen, oxygen, or sulfur atom in an aromatic ring. Unlessotherwise indicated, a heteroaryl group can be unsubstituted orsubstituted with one or more, and preferably one to four, substituentsselected from, for example, halo, alkyl, alkenyl, OCF₃, NO₂, CN, NC, OH,alkoxy, amino, CO₂H, CO₂alkyl, aryl, and heteroaryl. Examples ofheteroaryl groups include, but are not limited to, thienyl, furyl,pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl,triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl,benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

The conditions that permit cross metathesis (step (1a)) include usingruthenium and molybdenum based complexes capable of catalyzing olefinmetathesis. Cross metathesis catalysts include, but are not limited to,Grubbs' catalyst and Schrock's catalyst. Specific catalysts contemplatedinclude [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene] dichloro(phenylmethylene) (tricyclohexylphosphine) ruthenium and[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[[2-(1-methylethoxy)phenyl]methyleneruthenium. Other catalysts that can be used in the methods disclosedherein included those described in U.S. Pat. Nos.; 5110948; 5342909;6313365; 6316380; 6362357; 6369265; 6403801; 6403802; 6417363; 6426419;6500975; 6583307; 6586599; 6610626; 6613910; 6620955; 6635768; 6800170;6803429; 6818586; 6844442; 6867303; 6900347; 7026495; and 7205424.

Conditions that permit allylic amination (step (1b)) include reaction inthe presence of a transition metal catalyst. Specific catalystscontemplated include Pd-phosphine complexes such as, but not limited to,tetrakis(triphenylphosphine)palladium. The transition metal of thetransition metal catalyst used in allylic amination is typically Ni, Mo,Pt, Co, Ru, Rh, Ir, Mn, V, Cr, Ag, Fe, Cu or Pd. The ligands of thetransition metal catalyst contain a coordinating atom, through which theligand coordinates to the transition metal. The coordinating atomtypically is N, P or S, and possibly O or C. Examples of ligandsinclude, but are not limited to, cyclooctadiene, cycloheptatriene, CO,C₇H₈, and Cl. Examples of transition metal catalysts include, but arenot limited to, Pd catalysts, Ni(COD)₂, Mo(CO)₃(C₇H₈), Pt(PPh₃)₄,RhCl(PPh₃)₂, and CoCl₂. Pd catalysts are generally preferred transitionmetal catalysts for use in the allylic amination reaction. Examples ofsuitable nitrogen protecting groups for the allylic amination include,but are not limited to, C₆H₂-3,4,5-(OMe)₃, benzhydryl, PNP(p-nitrophenyl), Boc, and PMP (p-methoxyphenyl). Other suitable nitrogenprotecting groups can be found in Wuts et al., Greene's ProtectiveGroups in Organic Synthesis, 4^(th) ed., (Wiley Interscience: Hoboken,N.J.) 2007.

Suitable organic solvents for the allylic amination include, but are notlimited to, hexane, tetrahydrofuran, acetonitrile, dichloromethane,chlorobenzene, dichloroethane, toluene, ethyl acetate, methyl t-butylether, diethyl ether, or mixtures thereof. The allylic aminationreaction may also optionally be performed in the presence of a base.Examples of suitable bases include, but are not limited to,triethylamine and diisopropylethylamine.

Other conditions which permit allylic amination include those disclosedin the following Patent or Patent Publications: U.S. Pat. No. 7,173,157;U.S. Pat. No. 7,071,357; WO 2002/040491; and US 20060199728.

Conditions that permit reduction of the double bond (e.g., step (1c))include hydrogenation using hydrogen source and, optionally, a catalyst.Catalytic reduction can be carried out in a polar solvent, for examplein an alcohol such as methanol, ethanol, propanol and in water and anorganic acid, such as acetic acid, or mixture thereof. Catalysts used inreduction reaction under a hydrogen atmosphere are, for instance,palladium, platinum, Raney nickel, and the like. The hydrogen source istypically hydrogen gas, but can be some other reagent that permitsreduction of a double bond to a single bond.

In a second pathway for the synthesis of cinacalcet via allylicamination, a compound of formula (V) undergoes allylic amination to forma compound of formula (IV) trifluoromethylbenzaldehyde is reacted with avinyl reagent, prior to allylic amination and reduction, as depicted inScheme 2, below. Steps (2b) and (2c) can occur as described above forsteps (1b) and (1c).

In various embodiments of the methods described herein, the compound offormula (V) is prepared by admixing 3-trifluoromethylbenzaldehyde and avinyl nucleophile reagent (step (2a)) and optionally modifying theresulting vinyl alcohol to an ether, ester, or carbonate using knowntechniques, such that R² can be C₁₋₆alkyl, C(O)C₁₋₆alkyl,C(O)OC₁₋₆alkyl, or C(O)OC₁₋₆alkylenearyl. In specific embodiments, R²can be hydrogen, acetate, Boc, or CO₂Me. The conditions that permitnucleophilic attack by the vinyl reagent are typically anhydrous. In onespecific embodiment, vinyl lithium is admixed with3-trifluoromethylbenzaldehyde to form a compound of formula (V), whereinR² is hydrogen. Alternatively, compound (V) can be prepared by admixingvinyl chloride with magnesium metal (optionally in the presence ofiodine) to form vinyl magnesium chloride, which is then admixed with3-trifluoromethylbenzaldehyde to form a compound of formula (V), whereinR² is hydrogen. This intermediate is then optionally modified to give acompound of formula (V) wherein R² is acetate, Boc, or CO₂Me, prior tosubjecting the compound of formula (V) to allylic amination conditions.

C—O to C—N Rearrangement

Cinacalcet can alternatively be prepared using a C—O to C—Nrearrangement. In this synthetic approach, as outlined in Scheme 3, acompound of formula (V), wherein R² is hydrogen is admixed with areagent, such as 1-(1-naphthyl)ethyl isocyanate or a 1-(1-naphthyl)ethylcarbamoyl chloride, under appropriate conditions to form a compound offormula (VI) (step 3a). The compound of formula (VI) can then be admixedwith a catalyst under conditions that permit C—O to C—N rearrangement toform a compound of formula (IV) (step 3b). The compound of formula (IV)can subsequently undergo hydrogenation to form cinacalcet (step (3c)),as described above for step (1c).

The conditions that permit formation of a compound of formula (VI) (step(3a)) can include admixture in the presence of a metal catalyst, such asdescribed in Kim et al, Synlett, 3:261-262 (1998). In variousembodiments, step (3a) occurs in the presence of a base, such as metalalkoxides, alkyl lithiums, metal hydroxides, and the like.

The conditions that permit C—O to C—N rearrangement include contactingthe compound of formula (VI) with a metal catalyst that facilitates C—Oto C—N rearrangements. Such metal catalysts include Pd, Ru, Ni, Hg, Au,Ir, Rh, and Pt (see Mellegaard-Waetzig, et al., Synlett, 18:2759-2762(2005)). Specific conditions contemplated for the C—O to C—Nrearrangement include reaction in the presence oftetrakis(triphenylphosphine) palladium or (pentamethylcyclopentadienyl)ruthenium chloride tetramer.

Peptide Coupling

Cinacalcet can alternatively be prepared using peptide coupling methods.Such a synthetic route is outlined, below, in Scheme 4, starting from3-trifluoromethylcinnamic acid or a 3-trifluoromethyl dihydrocinnamicacid.

Peptide coupling (e.g., step (4a)) can occur under a variety ofconditions. Typically admixture of an acid or activated acid and anamine occurs in a compatible organic solvent, such as methylenechloride, THF, DMF, DMSO, ethyl acetate, or the like. Coupling reagentsthat facilitate the formation of an amide bond between an amine and acarboxylic acid can be employed. Preferred coupling agents include DCC,DIC, O-benzotriazolyl-1-yl-1,1,3,3-tetramethyluroniumhexafluorophosphate(HBTU),O-(7-azabenzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate(HATU); O-(7-azabenzotriazol-1-yl-1,1,3,3-bis (tetramethylene uroniumhexafluorphosphate (HApyU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(pentamethylene) uronium hexafluorophosphate (HApipU),O-(7-azabenzotrizol-1-yl)-1,3-dimethyl-1,3-trimethylene uroniumhexafluorophosphate (HAMTU), benzotriazolyl-yl-1,1,3,3-bis(tetramethylene uronium tetrafluoroborate)(TBTU), TFFH, or reagents thatform in situ acid chlorides, mixed anhydrides, EZDQ, active esters, suchas pentafluorophenyl or succinimide esters of the carboxylic acid.

For reduction of a compound of formula (VIIB) to cinacalcet, reductionof the double bond and of the carbonyl to a methylene moiety can occursimultaneously or serially under the same conditions or separateconditions. In various embodiments, the partially reducedintermediate—such as reduction of the double bond first to form anintermediate compound of formula (VIIA) or reduction of the carbonylfirst to form a compound of formula (IV)—is isolated prior to thesubsequent reduction to form cinacalcet, while in other embodiments, thepartially reduced intermediate is subsequently fully reduced to formcinacalcet without isolation and/or purification. Reduction of acarbonyl to a methylene moiety can be achieved by admixing the compoundof formula (VIIB) or formula (VIIA) with a reducing agent. Reducingagents include, but are not limited to, metal hydrides such as sodiumborohydride (NaBH₄), lithium borohydride (LiBH₄), calcium borohydride(Ca(BH₄)₂), lithium aluminum hydride (LiAlH₄) or complexes of BH₃ withTHF, Et₃N or Me₂S. The reduction of the double bond of the compound offormula (VII) can occur under the conditions described above, for step(1c).

Heck Couplings

Cinacalcet can be prepared by coupling of an aryl halide with anappropriate corresponding compound. Heck, Sonagashira, Suzuki, Hiyama,and Stille couplings are all contemplated as synthetic routes for thepreparation of cinacalcet. For Heck coupling, a compound of formula(VIII) is reacted with an allyl amine compound of formula (IX) or anacrylamide compound of formula (XI) under conditions that permitcoupling of the two compounds, to form a compound of formula (X) or acompound of formula (XII), respectively, as shown in Scheme 5. Forcompounds of formula (VIII), X can be a halogen (e.g., F, Cl, Br, or I),or can be a triflate (OSO₂CF₃), tosyl (OSO₂C₆H₄CH₃), mesyl (OSO₂CH₃),nonaflate (OSO₂C₄F₉) or any other functional group that is compatiblewith a Heck, Sonagashira, Suzuki, Hiyama, or Stille coupling.

Compounds of formulae (IX), (XI), (X), and (XII) can independently havean R selected from hydrogen, benzyl, substituted benzyl, BOC, Cbz, andacetate. R can be any amine protecting group compatible with the variousreaction conditions to which the compound is subjected. Suitable Rgroups (e.g., amine or amide protecting groups) include those disclosedin Greene's Protective Groups in Organic Synthesis, 4^(th) ed (2007).

The conditions that permit the Heck coupling between the compound offormula (VIII) and the allyl amine (IX) or acrylamide (XI) includeadmixture in the presence of a transition metal catalyst. Typically, thetransition metal catalyst comprises Pd or Ru. Specific Pd catalystsinclude Pd(OAc)₂, PdCl₂, Pd(dba)₃, and Pd(P(PAr₃)₄), wherein Ar is asubstituted or unsubstituted phenyl or a linked bi-phenyl phosphine,such as BINAP or dppp. Specific Ru catalysts include, but are notlimited to, [RuCl₂(p-cymene)]₂. Typically a polar organic solvent isused, such as DMF, methanol, acetonitrile, or mixtures thereof. Thetemperature can optionally be elevated to assist in formation of thecompound of formula (X) or (XII). Additionally, a base can also be addedto facilitate the Heck reaction. Bases include amine bases, such astriethylamine or diisopropylethylamine, or metal carbonates (e.g.,potassium carbonate), or metal acetates (e.g., sodium acetate).

The reduction of step (5b) can be performed under the conditions asdescribed above for step (1c) and/or step 4(b).

Alkyne Reduction

An alternate route to the synthesis of cinacalcet is outlined in Scheme6, below. It involves the reduction of an alkyne compound of formula(XIII) or formula (XVI) to form cinacalcet or a cinacalcet derivative.For compounds of formulae (XIII) or (XVI), R can be hydrogen, benzyl,substituted benzyl, Cbz, BOC, and acetate, or any amine protecting groupwhich is compatible with the reaction conditions to which the compoundis subjected. Suitable amine protecting groups include, but are notlimited to, those disclosed in Greene's Protective Groups in OrganicSynthesis, 4^(th) ed (2007).

The reduction conditions of step (6a) can be as those described abovefor steps (1c), (4b), or (5b). Similar to steps (4b) and (5b), thereduction of the alkyne compound of formula (XIII) or (XVI) can beachieved in a step-wise manner, with each successive reductionintermediate isolated prior to a subsequent reduction. For example, fora compound of formula (XIII), the carbonyl moiety of the compound can bereduced to a methylene moiety (to form a compound of formula (XVI))prior to reduction of the alkyne bond. The alkyne bond can be firstreduced to an alkene (to form a compound of formula (IV)), isolated assuch, then to an alkyl group to form cinacalcet. Alternatively, thealkyne compound of formula (XIII) can be reduced first, to an alkene (toform a compound of formula (VIIB)), isolated as such, then reduced to analkyl group (to form a compound of formula (VIIA)), and then thecarbonyl moiety can be reduced to form cinacalcet or a cinacalcetderivative.

In various embodiments, the compound of formula (XIII) is prepared priorto reduction to cinacalcet. Schemes 6A-6D outline several routes for thepreparation of a compound of formula (XIII) or (XVI).

The coupling of step (6Aa) or (6Ba) can be performed in the presence ofa transition metal catalyst. Such catalysts include a PdCl₂ catalysts,optionally having one or more phosphine ligands, and a co-catatlyst,such as a copper salt (e.g., CuI). An inorganic or amine base may alsobe used to facilitate the coupling of the compound of formula (VIII) and(XV) the propiolic acid or ester. Such bases include Et₃N, metalcarbonates (e.g., Cs₂CO₃), and metal bicarbonates (e.g., NaHCO₃). Otherconditions can be used which include exposing to microwave energy and/orheating to above 50° C.

Step (6Ab) can be performed using similar conditions for peptide bondformation as described above, for step (4a).

Alternatively, a compound of formula (XIII) can be prepared by reacting3-trifluoromethylphenyl acetylene and 1-(1-naphthyl)ethyl isocyanate. Invarious embodiments, 3-trifluoromethylphenyl acetylene is admixed with abase, such as n-butyl lithium or a Grignard reagent, to form adeprotonated acetylide. The acetylide is then admixed with theisocyanate to form the compound of formula (XIII), wherein R ishydrogen, as shown in Scheme 6C. Other conditions suitable forisocyanate coupling to form an amide applicable to the methods describedherein include those described in Debrabander et al., Tetrahedron,60:9635 (2004).

In various embodiments, the compound of formula (XVI) is prepared asoutlined in Scheme 6D. The Sonogashira coupling between a compound offormula (VIII) and a compound of formula (XVII), step (6Da), can providea compound of formula (XVI). The conditions for the Sonogashira couplingare as described above, for step (6Aa) or (6Ba). R can be a hydrogen, aC₁₋₆alkyl, or a nitrogen protecting group, such as a Boc, Fmoc, or Cbzgroup, that is stable to the Sonogashira coupling conditions. Suitableprotecting groups for nitrogen are discussed in detail in the Greene'sProtective Groups in Organic Synthesis, 4^(th) ed (2007).

Cross Metathesis

Cinacalcet can be prepared via cross-metathesis of a compound of formula(I) and a compound of formula (XVIII) to form a compound formula (IV),as shown below in Scheme 7. R¹ is independently selected from hydrogenand C₁₋₆alkyl. The conditions for the cross-metathesis step (7a) is asdescribed above for step (1a) and the conditions for forming cinacalcetfrom a compound of formula (IV) is described above for step (3c).

Hydroformylation

Cinacalcet can be prepared using hydroformylation, as depicted in Scheme8, below. In various embodiments, 3-(3-trifluoromethylphenyl)propanal isprepared (step (8a)), then admixed with 1-(1-naphthyl)ethylamine to forman imine (XX) (step (8b), which can be reduced to form cinacalcet (step(8c)). Hydroformylation conditions can include exposure to a mixture ofhydrogen gas and carbon monoxide in the presence of a metal catalyst.Typically, the metal is a cobalt or rhodium catalyst. Examples ofligands in the catalyst can include phosphine (PR₃, RC₆H₅, n-C₄H₉),phosphine oxide (O═P(C₆H₅)₃), phosphite, amine, amide, and isonitrile.Other conditions suitable for hydroformylation applicable to the methodsdescribed herein include those described in U.S. Pat. Nos. 4,148,830;4,717,775; 4,769,498, and WO 03/078444. The reduction of the compound offormula (XX) can be accomplished using the conditions as outlined abovefor steps (1c), or can be accomplished by reduction with a hydridereducing agent such as sodium borohydride, sodium(triacetoxyborohydride), sodium (cyanoborohydride), disobutylaluminiumhydride or lithium aluminium hydride

In various embodiments, the 3-trifluromethylstyrene, hydrogen, carbonmonoxide and 1-(1-naphthyl)ethyl amine are all admixed together to formcinacalcet without isolating the intermediate compound of formula (XX),as shown in Scheme 8A, below. The conditions of step (8Aa) are heatingthe substrates in the presence of [Rh(cod)₂]BF₄, and a phosphine ligandsuch as Xantphos under elevated pressure of carbon monoxide andhydrogen. Other conditions suitable for the hydroaminomethyalation aredescribed in Ahmed et al., J. Am. Chem. Soc. 125:10311 (2003) andBriggs, et al. Org. Lett., 7:4795 (2005).

Acrylamide Coupling

In various embodiments, cinacalcet can be synthesized as depicted inScheme 9, below. Coupling of compound (VIIIA) and compound (XIA) can beaccomplished by admixing compound (VIIIA) and compound (XIA) in thepresence of a rhodium catalyst to form compound (VII). Compound (VII)then can be reduced to form cinacalcet or a salt thereof.

For compound (VIIIA), X′ can be B(OH)₂, Si(OR³)₃, Sn(R³)₃, and Ti(OR³)₃,and R³ is the same or different and is independently selected from thegroup consisting of hydrogen and C₁₋₆alkyl.

The conditions that promote coupling of compounds (VIIIA) and (XIA) caninclude admixture of the compounds in the presence of a rhodium orpalladium catalyst. The rhodium catalyst can be a rhodium (I) catalyst,for example. Specific Rh catalysts include, but are not limited to,Rh(acac)(CO)₂, Rh(acac)(C₂H₄)₂, or Rh(acac). Specific Pd catalystsinclude Pd(OAc)₂, which can be coordinated to a nitrogen ligand, such asbipyridine, 1, 10-phenanthroline, and bisoxazolines. In a specific classof embodiments, the Rh catalyst can be coordinated to a phosphorusligand, such as PPh₃, PCy₃, BINAP, diop, chiraphos, MeO-mop, iPr-phox,or bppfa. Other conditions include those disclosed in Sakuma, et al., J.Org. Chem., 66:8944-8946 (2001), Hayashi, et al., Chem. Rev.,103:2829-2844 (2003), Lautens, et al., Synthesis, 12:2006-2014 (2004),and Lu, et al., J. Org. Chem., 70:9651-9653 (2005).

The conditions that permit reduction can include performing thereduction in the presence of a reducing agent. Reducing agents include,but are not limited to, metal hydrides such as sodium borohydride(NaBH₄), lithium borohydride (LiBH₄), calcium borohydride (Ca(BH₄)₂),lithium aluminum hydride (LiAlH₄) or complexes of BH₃ with THF, Et₃N orMe₂S.

Hydroboration

In various embodiments, cinacalcet can be synthesized as depicted inScheme 10, below. Hydroboration of 1-(3-trifluoromethylphenyl)-2-propeneis accomplished by admixing the allylbenzene with borane. Next,N-chloro-1-(1-naphthyl)ethylamine is added to the mixture to formcinacalcet.

Hydroboration conditions for step (10a) include hydroboration conditionssuch as those disclosed in Kabalka et al., J. Org. Chem, 49:1656 (1984).Boranes other than BH₃ can be used. Other boranes contemplated include,but are not limited to, hydroboration reagents R₂BH, such asdicyclohexylborane, diisopropylborane, disiamylborane,9-borabicyclo[3.3.1]nonane (“9-BBN”), and the like. Hydroborations aregenerically discussed in Miyaura er al. Chem. Reviews, 2457 2483 (1995).

Cinacalcet Salts

Cinacalcet can also be made by one or more of the methods disclosedherein and formulated as pharmaceutically acceptable salts (e.g., acidaddition salts) and complexes thereof. Pharmaceutically acceptable saltsare non-toxic salts at the concentration at which they are administered.The preparation of such salts can facilitate the pharmacological use byaltering the physical characteristic of the cinacalcet withoutpreventing it from exerting its physiological effect. Useful alterationsin physical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, hydrochloride, phosphate, sulfamate, acetate,citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.(See e.g., WO 92/020642.) Pharmaceutically acceptable salts can beobtained from acids such as hydrochloric acid, sulfuric acid, phosphoricacid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaricacid, malonic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid,and quinic acid. In preferred embodiments, the salt is the hydrochloridesalt.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free base form of a compound is dissolvedin a suitable solvent, such as an aqueous or aqueous-alcohol solution,containing the appropriate acid and then isolated by evaporating thesolution. In another example, a salt is prepared by reacting the freebase and acid in an organic solvent.

Cinacalcet Polymorphs

Three distinct crystalline forms of cinacalcet HCl are currently known,and are referred to herein as Forms I, II, and III, and can be referredto as “polymorphs.” Form II has been prepared but was unstable at roomtemperature. Since the intended use of cinacalcet is as atherapeutically active pharmaceutical agent, a stable andpharmaceutically acceptable form of this compound is a preferredembodiment.

Polymorphism can be characterized as the ability of a compound tocrystallize into different crystal forms, while maintaining the samechemical formula. A crystalline polymorph of a given drug substance ischemically identical to any other crystalline polymorph of that drugsubstance in containing the same atoms bonded to one another in the sameway, but differs in its crystal forms, which can affect one or morephysical properties, such as stability, solubility, melting point, bulkdensity, flow properties, bioavailability, etc. Thus, the term“polymorph” is used to refer to a crystalline form of a substance thatis distinct from another crystalline form but that shares the samechemical formula.

While the present invention particularly contemplates an isolatedcomposition of a purified cinacalcet hydrochloride polymorph III, it iscontemplated that the skilled person may prepare compositions in whichthe isolated, purified polymorph III is mixed with, for example,polymorph I or II.

In addition, in compositions for use in the present invention, it shouldbe understood that the skilled person may prepare pharmaceutical orother therapeutic compositions which comprise the polymorph IIIdescribed herein in combination with another agent that is used as acalcimimetic. Such combination therapy compositions may be used to havea combined effect as a calcimimetic combination therapy to produce adesired therapeutic, ameliorative, inhibitory or preventativePTH-lowering or calcium-lowering effect.

In the therapeutic embodiments of the invention, the compositions can beadministered and the effects of the compositions are routinely monitoredto avoid the subject becoming hypocalcemic; therefore lowering the serumcalcium levels to less than 7.8 mg/dL should be avoided. In otherembodiments, the calcimimetic therapy is administered to lower the PTHlevels in the subject, and the PTH levels are lowered to levels of about250 pg/ml. However, the therapies should be monitored and adjusted toavoid lowering the PTH levels to less than 150 pg/ml. Thus, thetherapies preferably are designed in order to lower and maintain the PTHlevels to a range of about 200 pg/ml to about 300 pg/ml.

Thus, in a typical treatment regimen, it is contemplated that a dailydose of the polymorph III is administered to achieve PTH levels in thesubject of about 150 pg/ml to about 300 pg/ml. Thus, in variousembodiments, the subject is initiated on a therapeutic regimen in whicha dosage form of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg isadministered daily. The PTH levels in the subject are monitored prior toand after administration of the composition. The dosage of the polymorphcan be increased to a level at which the dosage has the desiredtherapeutic effect of maintaining the level of PTH of about 200 pg/ml toabout 300 pg/ml. Where it is seen that the PTH levels in the subject arehigher than 300 pg/ml, the dosage of the polymorph administered may beincreased. If the level of the PTH is seen to be at or about 200 pg/ml,the dosage of the polymorph can be maintained or lowered. If the levelof the PTH is seen to be below 200 pg/ml, the dosage of the polymorphshould be lowered. The PTH concentration can be monitored and thepolymorph administration regimen reinitiated when and if the patient'sPTH levels again reach 300 pg/ml or greater. Likewise, the serum calciumlevels can be monitored in response to the treatment with the polymorphIII such that the serum calcium levels are maintained at or above thelower limit of the normal level of serum calcium, which is about 8.4mg/dL. If the blood work shows that the treatment with the polymorph isresulting in the decrease of serum calcium levels to the range ofbetween 7.8 mg/dL to about 8.4 mg/dL the dosage of the polymorph shouldbe decreased and/or combined with calcium-containing phosphate bindersand/or vitamin D sterols. If the calcium levels fall below 7.5 mg/dL thecalcimimetic therapy should be stopped and/or the amount of vitamin Dsterols and/or calcium-containing phosphate binders should be increaseduntil the serum calcium levels are again above 8.4 mg/dL.

As used herein, the term “amorphous” refers to samples lacking awell-defined peak or having a broad “halo” feature in the X-ray powderdiffraction (XRPD) pattern of the sample. The term “amorphous” may alsorefer to a material that contains too little crystal content to yield adiscernable pattern by XRPD or other diffraction techniques. Glassymaterials are contemplated to be amorphous. Amorphous materials do nothave a true crystal lattice, and are consequently glassy rather thantrue solids, technically resembling very viscous non-crystallineliquids. Rather than true solids, glasses may better be described asquasi-solid amorphous material. Thus, an amorphous material may refer toa quasi-solid glassy material. Precipitation of a compound fromsolution, often effected by rapid evaporation of solvent, is known tofavor amorphous forms of a compound.

As used herein, the term “broad” or “broadened” is used to describespectral lines (peaks) including XRPD, nuclear magnetic resonance (NMR)spectroscopy and infrared (IR) spectroscopy lines is a relative termthat relates to the line width of a baseline spectrum. The baselinespectrum is often that of an unmanipulated crystalline (defined below)form of a specific compound as obtained directly from a given set ofphysical and chemical conditions, including solvent composition andproperties such as temperature and pressure, for example describing theXRPD spectrum of ground or pulverized crystalline material relative tothe crystalline material prior to grinding. Line broadening isindicative of increased randomness in the orientation of the chemicalmoieties of the compound, thus indicative of an increased amorphouscontent. When comparisons are made between crystalline materialsobtained via different crystallization conditions, broadening indicateseither increased amorphous content of the sample having the broadenedspectral lines, or possibly a mixture of crystals that have similar,although not identical spectra.

The specific crystal form of the agent will dictate the thermodynamicstability of the crystal. Depending on the form of the specific type ofcrystal present, various amounts of amorphous solid material containingthe specific compound will be present. Such amorphous solid material maybe present as a side product of the initial crystallization, and/or aproduct of degradation of the crystals comprising the crystallinematerial. Thus, “crystalline” as used herein contemplates amorphouscontent of varying degrees so long as the material has a discernablediffraction pattern. Often the amorphous content of a crystallinematerial may be increased by grinding or pulverizing the material, whichis evidenced by broadening of diffraction and other spectral linesrelative to the unground crystalline material. Sufficient grindingand/or pulverizing may broaden the lines relative to the ungroundcrystalline material to the extent that the XRPD or other crystalspecific spectrum may become undiscernable, making the materialsubstantially amorphous, or barely discernable, which may be termedquasi-amorphous.

As used herein, the term “trace” refers to an amount that is detectableby the physical and chemical detection methods employed herein. Forexample, water, crystallization solvents, and amorphous forms ofcinacalcet may all be present in trace amounts of Form III while notsignificantly affecting the XRPD, NMR, or IR spectral measurements ofthe sample or its biological activity.

In some instances, the polymorph may be a crystalline anhydrate,monohydrate, or hemihydrate. Amorphous polymorphs can be derived byrapidly evaporating solvent from solvated cinacalcet, or by grinding,pulverizing or otherwise physically pressurizing or abrading any of thevarious crystalline amorphous forms described herein. General methodsfor precipitating and crystallizing organic compounds may be applied topreparing any cinacalcet polymorphs. These general methods are known tothose skilled in the art of synthetic organic chemistry andpharmaceutical formulation, and are described, for example, by J. March,“Advanced Organic Chemistry: Reactions, Mechanisms and Structure,” 4thEd. (New York: Wiley-Interscience, 1992).

In a specific class of embodiments, the Form III is prepared using “coldfinger sublimation.” Sublimation is the term used for transformation ofa compound directly from the solid to the gaseous state or from thegaseous to the solid state without becoming a liquid. The apparatus forperforming this process typically has a section where the compound to besublimed is placed and a cooler section above this section where thepurified material will collect. Typically, the compound is heated andcollected on a chilled piece called a cold finger, thus, the “coldfinger” is a common name for a chilled tubing used in the sublimationexperiment. In the preparation of cinacalcet form III, the solid Form Iis heated to gaseous state in a flask under vacuum and the crystal Formm accumulates on the surface of the cold finger that is inserted in theflask. Usually cooling water or dry ice are used to cool the coldfinger. Polymorph III may be obtained in the following manner.Sublimation of Form I leads to formation of Form III. Sublimation wascarried out on the Form I material on a laboratory scale using a coldfinger sublimation apparatus. The apparatus was immersed in a siliconeoil bath and the cold finger was water-cooled. The system was sealedunder vacuum. Vacuum was not released until the final solids wereharvested. The solids were observed through optical microscopy andcharacterized by XRPD analysis.

In another specific class of other embodiments, the Form III is preparedfrom melt-quenched amorphous material. In this process, Form I is meltedat approximately 190-200° C. It is then quenched in cold bath (dryice+acetone) for at least 15 minutes. The material is then ground into afine powder, which is then heated at 90° C. for approximately 3.5 hoursto produce the Form III.

Form III of cinacalcet is a metastable form. While a variety of solventsystems and crystallization methods were utilized, a short-range orderedmaterial was observed by XRPD analysis. The XRPD patterns observed inthe capillary screen were all similar to the pattern observed for theinitial Form III crystal. Additional thermal treatment of selectedcapillaries did not appear to produce a different material as determinedby optical microscopy and subsequent XRPD analysis.

Crystals of cinacalcet Form III suitable for structure determinationwere obtained from a cold finger sublimation of Form I solids. Thecrystal structure of Form III contains two cinacalcet HCl molecules inthe asymmetric unit. The difference between the two molecules is thatthe aromatic ring containing the trifluoromethyl group is rotatedapproximately 180°. The Form III molecules have a layered packing motifand are connected through one-dimensional hydrogen bonding interactions.

Preparation of amorphous samples was attempted through a number oftechniques: namely, melt/quench, spray drying and also cryogenicgrinding of Form I solids. All three techniques yielded the amorphousmaterial, which could then be used to prepare the Form III. Thecryogrind, melt/quench, and spray dried materials were analyzed by XRPD,but also could be analyzed by variable-temperature XRPD, to determine arelationship between the crystalline and short-range ordered materials.Pure Form III was readily prepared from amorphous material that is madeusing melt/quench and the spray dried techniques. The cryogenic grindingtechnique tends to yield mixtures of the Form I and Form III.

As noted above, one method of preparing Form III is to use melt-quenchedamorphous material. To prepare melt/quenched amorphous material, Form Iis melted at 190-200° C. It is then quenched in an ice bath (dryice+acetone) for at least 15 minutes. The process produces the amorphousmaterial which can then be used to prepare Form III.

In the cryogenic grinding procedure, Form I is freeze-milled underliquid nitrogen for approximately 40 minutes. This produces amorphousmaterial that can then be used to prepare Form III. The Form III isprepared by heating the amorphous form at 90° C. for 3.5 hours. Thisprocedure tends to yield a mixture of Form I and Form III.

In another exemplary procedure for preparing amorphous material,spray-drying can be used. In an exemplary spray drying technique 10mg/mL Form I solution in toluene solvent was spray dried and collectedunder the conditions shown in the following Table.

TABLE N₂ drying flow rate: 350 SLPM-550 SLPM (standard L/min) AtomPressure (N₂): 30-50 psi (lb/in²) (0.2-0.34 MPa) Inlet T: 165° C. OutletT: ~108° C. Flow rate: 0.5-1.0 mg/min Nozzle T (bath): 20° C. Cyclone T(bath): 20° C.

Again, the amorphous material that results from the spray dryingtechnique is then used to prepare Form III as discussed above, e.g.,heating at 90° C. for 3.5 hours.

X-ray powder diffraction analyses were performed using a ShimadzuXRD-6000 X-ray powder diffractometer using Cu Kα radiation. Theinstrument is equipped with a long fine focus X-ray tube. The tubevoltage and amperage were set to 40 kV and 40 mA, respectively. Thedivergence and scattering slits were set at 1° and the receiving slitwas set at 0.15 mm. Diffracted radiation was detected by a NaIscintillation detector. A θ-2θ continuous scan at 3°/min (0.4 sec/0.02°step) from 2.5° to 40°2θ was used. A silicon standard was analyzed tocheck the instrument alignment. Data were collected and analyzed usingXRD-6000 v. 4.1. Samples were prepared for analysis by placing them inan aluminum holder with silicon insert.

X-ray powder diffraction analyses also were performed using an InelXRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive)detector with a 2θ range of 120°. Real time data were collected usingCu-Kα radiation starting at approximately 4°2θ at a resolution of0.03°2θ. The tube voltage and amperage were set to 40 kV and 30 mA,respectively. The monochromator slit was set at 5 mm (or 2 mm) by 160μm. The pattern is displayed from 2.5°-40°2θ. Samples were prepared foranalysis by packing them into glass capillaries 1.0 mm in diameter. Eachcapillary was mounted onto a goniometer head that is motorized to permitspinning of the capillary during data acquisition. The samples wereanalyzed for 5 min. Instrument calibration was performed using a siliconreference standard.

X-ray powder diffraction analyses also were performed on preparedcapillaries using a Bruker D-8 Discover diffractometer and Bruker'sGeneral Area Diffraction Detection System (GADDS, v. 4.1.14). Anincident beam of Cu Kα radiation was produced using a fine-focus tube(40 kV, 40 mA), a Göbel mirror, and a 0.5 mm double-pinhole collimator.Capillaries were positioned on a capillary holder secured to atranslation stage. A video camera and laser were used to position thearea of interest to intersect the incident beam. Samples were analyzedin transmission mode using a constant detector angle (2θ) of 20°. Theincident beam was scanned 10° relative to the capillary surface normaland rastered ±1.0 mm along the length of the capillary during theanalysis. Scanning and rastering the incident beam optimizes orientationstatistics and maximizes the diffraction signal. Diffraction patternswere collected in 100 seconds using a Hi-Star area detector located14.94 cm from the sample and processed using GADDS. The intensity in theGADDS image of the diffraction pattern was integrated from approximately2° to 37° 2θ and from −163° to −17° chi using a step size of 0.04° 2θ.The integrated patterns display diffraction intensity as a function of2θ.

Variable-temperature XRPD (VT-XRPD) was performed on a Shimadzu XRD-6000X-ray powder diffractometer equipped with an Anton Paar HTK 1200 hightemperature stage. The sample was packed in a ceramic holder andanalyzed from 2.5° to 40°2θ at 3°/min (0.4 sec/0.02° step). Ramp ratesand hold times for each experiment may be varied and such variations areknown to those of skill in the art of operating X-ray powderdiffractometer equipment. A silicon standard was analyzed to check theinstrument alignment. Temperature calibration was performed usingvanillin and sulfapyridine standards. Data were collected and analyzedusing XRD-6000 v. 4.1. VT-XRPD was performed on as-received short-rangeordered material as well as materials prepared through quenching of amelt and cryogenic grinding.

Differential scanning calorimetry (DSC) also can be performed for thecrystalline materials using a TA Instruments differential scanningcalorimeter 2920, or other similar instrument. The sample was placedinto an aluminum DSC pan, and the weight accurately recorded. The panwas covered with a lid and then crimped. In such an analysis, the samplecell is equilibrated at 25° C. and heated under a nitrogen purge at arate of 10° C./min. The crystalline material is typically heated to 350°C., and transition maxima temperatures are noted.

Thermogravimetric (TG) analysis can be performed for crystallinematerial using a TA Instruments 2950 thermogravimetric analyzer or othersimilar instrument. The sample is placed in an aluminum sample pan andinserted into the TG furnace. The furnace is first equilibrated at 25°C., then heated under nitrogen at a rate of 10° C./min, up to a finaltemperature of 350° C. Nickel and Alumel™ can be used as the calibrationstandards.

FT-Raman spectrum also can be acquired for the polymorph III on anFT-Raman 960 spectrometer (Thermo Nicolet) or other similar instrument.This spectrometer uses an excitation wavelength of 1064 nm.Approximately 0.7 W of Nd:YVO4 laser power is used to irradiate thesample. The Raman spectrum is measured with an indium gallium arsenide(InGaAs) detector. The sample is prepared for analysis by placing thematerial in a glass tube and positioning the tube in a gold-coated tubeholder in the accessory. Sample scans (e.g., typically in the order ofapproximately 250 sample scans) are collected from 3600-98 cm⁻¹ at aspectral resolution of 4 cm⁻¹, using Happ-Genzel apodization. Wavelengthcalibration was performed using sulfur and cyclohexane.

For NMR analysis, a solution ¹H nuclear magnetic resonance (NMR)spectrum can be acquired at ambient temperature using e.g., a Varian^(UNITY)INOVA-400 or other similar spectrometer at a ¹H Larmor frequencyof 399.804 MHz. The sample is dissolved in DMSO-d₆. The spectrum isacquired with a ¹H pulse width of 7.8 μs, a 2.50 second acquisitiontime, a 5 second delay between scans, a spectral width of 6400 Hz with32000 data points, and 40 co-added scans. The free induction decay (FID)is processed using the Varian VNMR 6.1C software with 65536 points andan exponential line broadening factor of 0.2 Hz to improve thesignal-to-noise ratio. The residual peak from incompletely deuteratedDMSO is typically seen at approximately 2.50 ppm. The spectum can bereferenced with an internal reference, e.g., to internaltetramethylsilane (TMS) at 0.0 ppm.

The crystalline material also may be characterized using opticalmicroscopy e.g., performed with a Leica DM LP polarizing microscope (orother similar instrument), with a 5.0× objective, crossed-polarizers anda first order red compensator and Leica stereoscopes, with 0.8× to 10×objectives, with and without crossed-polarizers and a first order redcompensator. Samples can be viewed in vials or glass microbeakers, or oncoverglasses or glass slides (often with a drop of the cryoprotectantPARATONE-N).

Pharmaceutical Compositions and Therapy Using Cinacalcet

The disclosure further provides pharmaceutical compositions andformulations using such polymorphs. The pharmaceutical compositions andformulations are adapted for various forms of administration includingoral, injection and/or inhalation. The disclosure also provides methodsfor making cinacalcet hydrochloride polymorph, methods of manufacturingpharmaceutical formulations of cinacalcet hydrochloride polymorph andmethods of treating various diseases such as, for example, HPT,parathyroid carcinoma, and other hypercalcemia-related disorders.

“Effective” or “therapeutically effective” is meant to describe apolymorph of a compound or a composition of the present inventioneffective as a calcimimetic and thus producing the desired therapeutic,ameliorative, inhibitory or preventative effect of Sensipar®. While thelevel or degree of calcimimetic, therapeutic, ameliorative, inhibitoryor preventative effect in various embodiments is the same or better thanthat seen when Sensipar® is used, the level or degree of such an effectmay be less than that observed with Sensipar® as long as it is morethan, or better than the effect seen in the absence of any calcimimetic.The “effect” may be a biochemical physiologic effect such as a loweringof serum calcium levels in a hypercalcemic patient, lowering of PTHlevels, or lowering of serum phosphorus levels. Alternatively, the“effect” may be one that is observed as a result of achieving atherapeutic lowering of serum calcium levels, PTH levels and the like,such as for example, an amelioration of the symptoms of CKD, a decreasein symptoms associated with increased calcium levels (e.g., lowering ofanxiety, depression, nausea, vomiting, bone fractures, kidney stones,vascular or soft-tissue calcification, and in some cases decreasedlikelihood of coma).

In one aspect, the polymorph Form III of the invention is able tomodulate calcium receptor activity and is used in the treatment ofdiseases or disorders which can be affected by modulating one or moreactivities of a calcium receptor. As noted above, Ca²⁺ levels aretightly controlled and Ca²⁺ levels in turn control various processessuch as blood clotting, nerve and muscle excitability, and proper boneformation. For example, extracellular Ca²⁺ inhibits the secretion ofparathyroid hormone from parathyroid cells, inhibits bone resorption byosteoclasts, and stimulates secretion of calcitonin from C-cells. In oneaspect, the disease or disorder to be treated by cinacalcet can becharacterized by abnormal bone and mineral homeostasis, such as calciumhomeostasis. Abnormal calcium homeostasis is characterized by one ormore of the following activities: (1) an abnormal increase or decreasein serum calcium; (2) an abnormal increase or decrease in urinaryexcretion of calcium; (3) an abnormal increase or decrease in bonecalcium levels, for example, as assessed by bone mineral densitymeasurements; (4) an abnormal absorption of dietary calcium; (5) anabnormal increase or decrease in the production and/or release ofmessengers which affect serum calcium levels such as parathyroid hormoneand calcitonin; and (6) an abnormal change in the response elicited bymessengers which affect serum calcium levels. The abnormal increase ordecrease in these different aspects of calcium homeostasis is relativeto that occurring in the general population and is generally associatedwith a disease or disorder.

Specific diseases and disorders which might be treated or prevented,based upon the affected cells, also include those of the central nervoussystem such as seizures, stroke, head trauma, spinal cord injury,hypoxia-induced nerve cell damage such as in cardiac arrest or neonataldistress, epilepsy, neurodegenerative diseases such as Alzheimer'sdisease, Huntington's disease and Parkinson's disease, dementia, muscletension, depression, anxiety, panic disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, schizophrenia, neurolepticmalignant syndrome, and Tourette's syndrome; diseases involving excesswater reabsorption by the kidney such as syndrome of inappropriate ADHsecretion (SIADH), cirrhosis, congestive heart failure, and nephrosis;hypertension; preventing and/or decreasing renal toxicity from cationicantibiotics (e.g., aminoglycoside antibiotics); and autoimmune diseasesand organ transplant rejection. In addition, bone and mineral-relateddisorders (as described in Coe and Favus, Disorders of Bone and MineralMetabolism, Raven Press, 1990), kidney diseases, endocrine diseases,cancer, cardiovascular diseases, neurological diseases, and diseasesassociated with gestation also can be treated.

In certain embodiments, the compositions will be useful in treating orameliorating psoriasis by reducing the proliferation of the abnormalskin cells. In other embodiments, the compositions may be used to reducewater retention in states of vasopressin excess, such as the syndrome ofinappropriate vasopressin (ADH) secretion. Polymorph III may be usefulfor treating hypertension by: (a) reducing renin secretion and/or (b) bystimulating production of vasodilators such as PTHrP (PTH-relatedpeptide) by vascular smooth muscle. It also is contemplated that thepolymorph Form III may be used to increase platelet aggregability, whichmay be useful when platelet counts are low. Calcium also is known topromote differentiation of colon and mammary cells, as such thepolymorph Form III may be expected to reduce the risk of colon or breastcancer. As a calcimimetic, cinacalcet Form III is expected to have auseful hypocalcemic action in the therapy of hypercalcemic disorders.The inhibitory effect of calcimimetics on osteoclasts and theirstimulation of the secretion of the hypocalcemic peptide calcitonin makethem useful in the therapy of hypercalcemia and its symptoms. Thecinacalcet Form III also improves hypocalcemic symptoms by activatingcalcium receptors. In addition, calcium suppresses the formation of1,25-dihydroxyvitamin D in the proximal renal tubule, and this vitamin Dmetabolite is frequently overproduced in renal stone patients andcontributes to their hypercalciuria. Suppression of1,25-dihydroxyvitamin D formation by a calcimimetic such as cinacalcetForm III is expected to be useful in treating renal calcium stonedisease.

The therapeutic cinacalcet Form III preparations will likely be used inthe treatment of human subjects but it should be understood thatveterinary treatments also are contemplated and the compositions may beused to treat other primates, farm animals such as swine, cattle, andpoultry; and sports animals and pets such as horses, dogs and cats.

For additional methods and compositions for using cinacalcet-relatedcompositions and diseases to be treated by such compositions, those ofskill are referred to U.S. Pat. Nos. 6,011,068; 6,031,003; 6,211,244;6,313,146.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

EXAMPLES

The present invention is further explained by the following exampleswhich should not be construed by way of limiting the scope of thepresent invention.

Example 1 Allylic Amination

(R)-(1-Naphthyl)ethylamine (257 mg, 1.5 mmol) and 3-trifluoromethylcinnamyl acetate (244 mg, 1 mmol) were charged to a 15 mL flask.Tetrahydrofuran (THF, 2 mL) and tetrakis(triphenylphosphine)palladium(58 mg, 5 mol %) were added, and the flask was purged with nitrogen. Thereaction mixture was stirred at room temperature for 16 h. The solventswere evaporated under vacuum and the residue was dissolved indichloromethane (10 mL). The organic phase was washed with saturatedsodium bicarbonate (5 mL) and the aqueous phase was back extracted withdichloromethane (5 mL). The organic layers were dried over magnesiumsulfate and evaporated to dryness. Chromatography on silica gel usingdichloromethane:methanol (50:1) as eluent afforded the desired(R)-(1-naphthalen-1-yl-ethyl)-[(E)-3-(3-trifluoromethyl-phenyl)-allyl}-amine(294 mg, 98.1% HPLC purity at 254 nm, 83% uncorrected yield). Theproduct was contaminated by some triphenylphosphine. The dialkylatedproduct was formed as a byproduct as well.

This reaction was also performed with the branched allylic acetate.Under non-optimized conditions, the HPLC showed 40% of theN-monoalkylated product and 54.7% of the N,N-dialkylated product.

The allylic amine was then reduced in the presence of palladium oncarbon and hydrogen gas in methanol to cinacalcet. The allylic amine(Didehydro-Sensipar®) (252 mg, 0.709 mmol), palladium (10 wt % oncharcoal, 25 mg), and methanol (5 mL) were charged in a 15 mL flask. Thereaction mixture was stirred under an atmosphere of hydrogen for 14 h.The reaction mixture was filtered through a plug of Celite® and thenconcentrated. Chromatography on silica gel using dichloromethane :methanol (20:1) as eluant afforded cinacalcet (229 mg, 89.3% purity byHPLC at 254 nm, 90% uncorrected yield). The product was contaminatedwith some triphenylphosphine.

Alternatively, cinacalcet was synthesized by a cross-coupling reactionbetween (R)-(+)-1-(1-napthyl)ethylamine and1-(3-trifluoromethyl-phenyl)-prop-2-en-1-ol. The1-(3-trifluoromethyl-phenyl)-prop-2-en-1-ol was synthesized as follows

To a 1.0 M THF solution of vinylmagnesium bromide (2.2 equiv.; 37.9mmol; 37.9 mL) cooled to 0-5° C. over an ice/water bath, was added3-(trifluoromethyl)benzaldehyde (1.0 equiv.; 17.23 mmol; 2.29 mL) over 2minutes. The cold bath was removed after 15 minutes and the reaction wasstirred at room temperature for 2 hours. The reaction was quenched withan aqueous ammonium chloride solution. The solvent was removed in vacuo.The aqueous layer was extracted three times with 20 mL dichloromethane.The organic layer was dried over sodium sulfate, filtered and thesolvent removed in vacuo. Isolated 3.17 g; as a yellow liquid, yield91%. The product identity was confirmed by ¹H NMR (400 MHz, CDCl₃) δ ppm2.25 (br. S., 1H) 5.17-5.28 (m, 2H) 5.30-5.43 (m, 1H) 5.93-6.09 (m, 1H)7.40-7.59 (m, 3H) 7.64 (s, 1H).

The 1-(3-trifluoromethyl-phenyl)-prop-2-en-1-ol was then allowed toreact with (R)-(+)-1-(1-napthyl)ethylamine to synthesize cinacalcet. Ina representative method, a dioxane solution (5 mL) of the1-(3-trifluoromethyl-phenyl)-prop-2-en-1-ol (1.0 equiv.; 1.0 mmol;202.17 mg) and (R)-(+)-1-(1-napthyl)ethylamine (1.5 equiv.; 1.5 mmol;0.241 mL) was charged the catalyst Pt(cod)Cl2 (1.0 mol %; 3.7 mg) andthe ligand DPEphos (2 mol5; 10.8 mg). The reaction mixture was refluxedunder an atmosphere of nitrogen for 15 hours, after which time it wasdiluted with water followed by extraction with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate and filtered.The solvent was removed in vacuo to give a yellow oil which was purifiedby silica gel chromatography with dichloromethane/methanol (49:1).Yield: Isolated 159 mg; 44% as a yellow oil. Product identity wasconfirmed by LC/MS (M+1): 356.4

Example 2 Peptide Coupling

In an alternative embodiment the present invention provides amethodology for synthesizing cinacalcet by a reaction between theappropriate amine and a pre-activated carboxylic acid.

The reaction was initiated by the addition of trans-3-trifluromethylcinnamoyl chloride (1.0 equiv.; 21.3 mmol; 5 g) to a stirred solution of(R)-(+)-1-(1-napthyl)ethylamine (1.1 equiv.; 23.4 mmol; 4 g) andtriethylamine (1.1 equiv.; 23.4 mmol; 3.26 mL) in toluene (100 mL) in aninert atmosphere of nitrogen. After stirring for 2 hours at roomtemperature, water (100 mL) was added to precipitate the crude productas a white solid. The solid was filtered and dried in a vacuum oven overnight at 55° C. Yield: 82%; 6.49 g. The identity of(E)-N-((R)-1-Naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamidewas confirmed by ¹H NMR (400 MHz, CDCl₃) and high resolution massspectrometry. δ ppm 1.76 (d, 3H) 5.85 (d, 1H) 6.08 (quin, 1H) 6.39 (d,1H) 7.43-7.73 (m, 9H) 7.80-7.91 (m, 2H) 8.14 (d, 1H) and HRMS (M+1):370.1.

In a variation of the foregoing method, the carboxylic acid can beactivated in situ during the coupling reaction. For example, a3-(trifluoromethyl)-cinnamic acid (1.0 equiv.; 2.3 mmol; 0.5 g) wasactivated using 1,1′-carbonyldiimidazole (1.3 equiv.; 3.0 mmol; 0.49 g)in ethyl acteate (EtOAc 10 mL). After stirring at room temperature for 3hours, was added a solution of (R)-(+)-1-(1-napthyl)ethylamine (1.2equiv.; 2.78 mmol; 0.45 mL). The reaction mixture was stirred at roomtemperature for an additional hour, with the progress of the couplingreaction monitored by LC/MS. The crude solution yield was 14% and theidentity of the product was confirmed by RRT and LC/MS (M+1): 370.0.

Reduction of the carbon-carbon double bond and amide group was carriedout using borane as the reducing agent.

To a suspension of(E)-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide(1.0 equiv.; 0.27 mmol; 100 mg) in toluene (1 mL) was addedborane-methyl sulfide complex as a 2.OM solution in toluene (1.5 equiv.;0.44 mmol; 0.22 mL). The reaction was heated under a nitrogen atmosphereto 50° C. for 3 hours before cooling and adding 2.5N HCl (1 mL).Subsequent heating of the reaction mixture at 50° C. for 1 hour afterthe addition of acid, followed by analysis of the cooled reactionmixture high performance liquid chromatography-mass spectrometricdetection afforded the desired saturated product. Solution yield: 93%.Confirmed identity by RRT and LC/MS (M+1): 358.4.

Alternatively, a hydride donor such as diisobutylaluminum hydride(DIBAL) can be used as the reducing agent.

Accordingly, diisobutylaluminum hydride as a 1.0 M solution in DCM (4.25equiv.; 5.75 mmol; 5.75 mL) was added via a syringe to a stirredsuspension of(E)-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide(1.0 equiv.; 1.36 mmol; 0.5 g) in toluene (10 mL) under an inertnitrogren atmosphere. The reaction was heated to 50° C. for 90 minutes,while periodically monitoring the progress of the reaction by HPLC.Solution yield: 60%. Confirmed identity by RRT and LC/MS (M+1): 358.4

In yet another variation, the reduction of the double bond and amidecarbonyl of(E)-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamideis carried out in a stepwise manner. Either the carbonyl group or thealkene double bond can be reduced first. For example, the reduction ofthe alkene double bond is achieved by hydrogenation in the presence of ametal catalyst.

A suspension of(E)-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide(1.0 equiv.; 0.67 mmol; 250 mg) and Pd/C 10 wt % (25 mg) was stirred ina mixture of methanol and toluene (7 mL/1 mL). The reaction flask wasevacuated and back filled using a hydrogen filled balloon (three times).The reaction mixture is stirred at room temperature and the progress ofthe reaction was monitored using high performance liquid chromatography.After 90 minutes, the reaction mixture was filtered over a bed of celiteand the solvent from the filtrate was removed in vacuo. The resultingsolid was dried overnight at 45° C. using a vacuum oven. Isolated yield:91.2% (229 mg). The identity of the amide was confirmed by ¹H NMR andmass spectrometry. (400 MHz, CDCl₃) δ ppm 1.60 (d, 3H) 2.39-2.53 (m, 2H)2.96-3.13 (m, 2H) 5.55 (br. S., 1H) 5.87-5.96 (m, 1H) 7.29-7.38 (m, 2H)7.39-7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, 1H) 7.83-7.89 (m, 1H)8.00-8.07 (m, 1H) and HRMS (M+1): 372.1

The isolated amide is then reduced to the corresponding saturated analog(methylene moiety) using a hydride donor such as lithium aluminumhydride, sodium borohydride, or calcium hydride, as the reducing agent.

Example 3 Metal Catalyzed Cross-Coupling Reaction

Cinacalcet can be synthesized via a metal catalyzed coupling reactionbetween an appropriately substituted aryl halide andN-((R)-1-Naphthalen-1-yl-ethyl)-acrylamide. The acrylamide wassynthesized by adding acryloyl chloride (1.2 equiv.; 17.5 mmol; 1.58 g)via syringe to an ice cold solution of (R)-(+)-1-(1-napthyl)ethylamine(2.50 g, 14.6 mmol, 1.0 eq.), and triethylamine (1.2 equiv.; 17.5 mmol;1.77 g) in toluene (50 ml). After the addition of acryloyl chloride iscomplete, the reaction mixture was allowed to warm to room temperature.The reaction was quenched after stirring for an hour at room temperatureby adding water (50 mL) to the reaction mixture. The crude product whichprecipitates out was filtered and dried in vacuo. Crude yield 79%; 3.1g. The identity of the product was confirmed by ¹H NMR and LC/MS. (400MHz, CDCl₃) δ ppm 1.72 (d, 3H) 5.63 (dd, 1H) 5.68-5.78 (m, 1H) 5.96-6.08(m, 2H) 6.31 (dd, 1H) 7.42-7.59 (m, 4H) 7.77-7.89 (m, 2H) 8.11 (d, 1H)and LC/MS (M+1): 226.1.

Cinacalcet was synthesized by reacting the acrylamide with1-bromo-3-(trifluoromethyl)benzene using metal catalyzed cross-couplingconditions. In one embodiment,N-((R)-1-naphthalen-1-yl-ethyl)-acrylamide (1.0 equiv.; 0.44 mmol;1OOmg), palladium (II) acetate (5 mo l%; 4.9 mg), tri-o-tolylphosphine(0.1 equiv.; 0.44 mmol; 13.4 mg) were suspended in acetonitrile (25 mL).To this suspension was added 1-bromo-3-(trifluoromethyl)benzene (1.0equiv.; 0.44 mmol; 99 mg) and triethylamine (30 equiv.; 13.2 mmol; 1.8mL) via syringe. The reaction was heated at reflux for 16 hours toafford(E)-N-((R)-1-Naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamideas the product. Solution yield: 79%. Confirmed identity by RRT and LC/MS(M+1): 370.4.

An alternative cross-coupling strategy for synthesizing cinacalcetinvolves the reaction of 3-(trifluoromethyl)phenyl boronic acid (3.0equiv.; 3 mmol; 0.57 g) with N-((R)-1-naphthalen-1-yl-ethyl)-acrylamide(1.0 equiv.; 1.0 mmol; 225 mg), in the presence of palladium (II)acetate (5 mol %; 11.2 mg) and 2,2-dipyridyl (10 mol %; 15.6 mg) inglacial acetic acid (2 mL) as the catalyst. The reaction is carried outby heating the mixture under a nitrogen atmosphere at 40° C. for 3 days.At the end of the reaction the crude mixture was diluted with methanolin a volumetric flask for quantitative analysis. Solution yield: 9.1%.Confirmed identity by RRT, LCMS (M+1): 370.4

Example 4 Alkyne Reduction

The invention also provides, in another embodiment, an alternative routefor synthesizing cinacalcet via the reduction of an alkyne precursor.The precursor is obtained by reacting an aryl acetylene with anappropriately substituted isocyanate. For example, a solution of3-ethynyl-α,α,α-trifluorotoluene (0.73 mL; 5.06 mmol; 2.0 equiv.) inanhydrous THF (20 mL) was cooled to −78° C. (acetone/dry ice bath). Ahexane solution of n-BuLi (1.6 M, 2.69 mL; 4.30 mmol; 1.7 equiv.) isthen added and the reaction mixture stirred at −78° C. for 30 minutes. Asolution of (R)-1-(1-isocyanatoethyl)naphthalene (1.0 equiv.; 2.53 mmol; 0.447 mL) in THF is then added to the reaction mixture which isstirred for an additional 30 minutes at −78° C. The reaction is stoppedby the addition of an aqueous solution of ammonium chloride to theorganic mixture. The organic layer is repeatedly extracted with water,dried over magnesium sulfate and the solvent removed in vacuo to afford3-(3-Trifluoromethyl-phenyl)-propynoic acid((R)-1-naphthalen-1-yl-ethyl)-amide as product. Isolated 830 mg, 89.2%yield. The identity of the product is confirmed by ¹H NMR and highresolution mass spectrometry. (300MHz, CDCl₃) δ ppm 1.77 (d, 3H)5.97-6.08 (m, 1H) 6.15 (br. S., 1H) 7.42-7.70 (m, 7H) 7.75 (s, 1H)7.81-7.94 (m, 2H) 8.12 (d, 1H) and HRMS (M+1): 368.1

Cinacalcet is obtained by reducing the alkyne-amide precursor. In oneembodiment, the alkyne was reduced by metal catalyzed hydrogenation.Specifically, to a methanolic solution (7 mL) of3-(3-trifluoromethyl-phenyl)-propynoic acid((R)-1-naphthalen-1-yl-ethyl)-amide (1.0 equiv.; 0.68 mmol; 250 mg) in atwo necked round bottom flask was added Pd/C 10 wt % (28 mg). The flaskwas evacuated and back filled using a hydrogen filled balloon (threetimes) before stirring the reaction mixture at room temperature under apositive pressure of hydrogen. Progress of the reaction was monitored byHPLC and LC/MS, with complete reduction of the alkyne group after 1hour. The reaction was stopped by filtering the reaction mixture over abed of celite, and the solvent was removed to give a solid that wasfurther dried at 45° C. overnight in vacuo. Product identity wasconfirmed by IH NMR and LC/MS. A quantitative yield of the product wasobtained (224 mg). (400 MHz, CDC1₃) δ ppm 1.60 (d, 3H) 2.39-2.53 (m, 2H)2.96-3.13 (m, 2H) 5.55 (br. S., 1H) 5.87-5.96 (m, 1H) 7.29-7.38 (m, 2H)7.39-7.46 (m, 4H) 7.46-7.55 (m, 2H) 7.76-7.82 (m, 1H) 7.83-7.89 (m, 1H)8.00-8.07 (m, 1H) and LC/MS (M+1): 372.0.

In an alternative embodiment, diborane was used as the reducing agent.Accordingly, to a stirred suspension of3-(3-trifluoromethyl-phenyl)-propynoic acid((R)-1-naphthalen-1-yl-ethyl)-amide (1.0 equiv.; 0.27 mmol; 100.8 mg) intoluene (2 mL) under nitrogen, was added using a borane-methyl sulfidecomplex as a 2.0 M solution in toluene (2.5 equiv.; 0.68 mmol; 0.34 mL).The reaction was heated to 50° C. for 7 hours, and then quenched usingIN solution of HCl (1 mL) and MeOH (1 mL). The quenched reaction mixturewas reheated to 90° C. for 4 hours, after which the solvent was removedin vacuo. The resulting residue was diluted with MeOH and analyzed usingLC/MS and RRT to confirm the identity of the final product. Solutionyield: 22%, LC/MS (M+1): 358.4

Example 5 Hydroformylation

In yet another embodiment, cinacalcet was synthesized via ahydroformylation reaction.

Accordingly, to a high pressure stainless steel reaction vessel(ChemScan Reactor System) was added 3-(trifluoromethyl)styrene (2.0equiv.; 3.5 mmol; 0.520 mL), (R)-(+)-1-(1-Napthyl)ethylamine (1.0equiv.; 1.75 mmol; 0.281 mL), Xantphos (4 mol %; 40.5 mg) and[Rh(cod)₂]BF₄ (1 mol %; 7.1 mg) in a mixture of toluene and methanol(1:1; 4 mL). The vessel was pressurized to 40 bar with SynGas (CO/H₂)and heated to 125° C. for 8 hours. A sample was prepared for analysis bydiluting the reaction mixture prior to injection onto an HPLC system.Solution yield: 53.8%. The identity of the product was confirmed by RRTand LCMS (M+1): 358.1.

Example 6 Alkene Metathesis

The invention further provides a synthetic methodology for cinacalcetbased on a metal catalyzed alkene metathesis reaction between a styreneanalog and an acrylamide derivative. Accordingly,3-(trifluoromethyl)styrene (1.0 equiv.; 0.44 mmol; 0.065 mL),N-((R)-1-naphthalen-1-yl-ethyl)-acrylamide (1.0 equiv.; 0.44 mmol; 100mg) and Grubbs second generation catalyst (15 mol %; 56 mg) in toluene(0.5 mL) were added to a 10 mL flask equipped with a condenser. Themixture was stirred under an inert atmosphere at 85° C. for 7 hours. Thesolvent was removed in vacuo and the residue was diluted in a volumetricflask with methanol. Product identity was confirmed by RRT and LC/MS(M+1): 370.4. Percent solution yield based on the chromatogram was 6.9%.

1. A method for the preparation of cinacalcet or a salt thereof comprising: a) admixing a compound of formula (I) and a compound of formula (II) under conditions that permit cross-metathesis to produce a compound of formula (III):

wherein each R¹ is the same or different and is selected from the group consisting of hydrogen, C₁-C₆ alkyl, OC₁-C₆alkyl, aryl, O-aryl, heteroaryl, and O-heteroaryl; b) admixing compound (III) and 1-(1-naphthyl)ethylamine under conditions to permit allylic amination to produce a compound of formula (IV)

and c) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
 2. The method of claim 1, wherein the conditions that permit cross-metathesis in step (a) comprise performing said cross-metathesis in the presence of a Ru catalyst.
 3. The method of claim 1, wherein the conditions that permit allylic amination in step (b) comprise performing said allylic amination in the presence of a Pd, Ru, Ir, Pt, Rh, or Ni catalyst.
 4. The method of claim 1, wherein the conditions that permit reduction in step (c) comprise performing said reduction in the presence of hydrogen and a Pd, Ni, Ir, Pt, Rh, or Ru catalyst.
 5. The method of claim 1, wherein the product of said method is cinacalcet hydrochloride.
 6. A method for the preparation of cinacalcet or a salt thereof comprising: a) admixing a compound of formula (V) and 1-(1-naphthyl)ethylamine under conditions to permit allylic amination to produce a compound of formulation (IV):

wherein R² is selected from the group consisting of hydrogen, C₁-C₆alkyl, aryl, heteroaryl, C(O)C₁-C₆ alkyl, C(O)aryl, C(O)heteroaryl, and C(O)OC₁-C₆ alkyl; and b) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
 7. The method of claim 6, further comprising admixing 3-trifluoromethyl-benzaldehyde and a vinyl reagent to form a compound of formula (V).
 8. The method of claim 7, wherein the vinyl reagent is selected from the group consisting of vinyl lithium and vinyl magnesium chloride.
 9. The method of claim 6, wherein the conditions that permit allylic amination in step (a) comprise performing said allylic amination in the presence of a Pd catalyst.
 10. The method of claim 6, wherein the conditions that permit reduction in step (b) comprise performing said reduction in the presence of hydrogen and a Pd, Ru, Ir, Pt, Rh, or Ni catalyst.
 11. The method of claim 6, wherein the product of said method is cinacalcet hydrochloride.
 12. A method for the preparation of cinacalcet or a salt thereof comprising: a) admixing a compound of formula (V), where R² is hydrogen, and 1-(1-naphthyl)ethyl isocyanate under conditions that permit the formation of a compound of formula (VI):

b) admixing compound (VI) and a catalyst under conditions that permit C—O to C—N rearrangement to form a compound of formula (IV)

and c) reducing compound (IV) under conditions that permit reduction to produce cinacalcet or a salt thereof.
 13. The method of claim 12, wherein the conditions that permit C—O to C—N rearrangement in step (b) comprise performing said C—O to C—N rearrangement in the presence of a metal catalyst, wherein the metal catalyst is selected from the group consisting of Pd, Ru, Ni, Ir, Rh, Hg, Au, and Pt.
 14. The method of claim 12, wherein the conditions that permit reduction in step (c) comprise performing said reduction in the presence of hydrogen and a Pd, Ni, Pt, Rh, Ru, or Ir catalyst.
 15. The method of claim 12, wherein the product of said method is cinacalcet hydrochloride.
 16. A method for the preparation of cinacalcet or a salt thereof comprising: a) admixing 3-trifluoromethyl-cinnamic acid and 1-(1-naphthyl)ethylamine under conditions to permit amide bond formation to form a compound of formula (VIIB)

and b) reducing compound (VIIB) under conditions that permit reduction to form cinacalcet or a salt thereof.
 17. The method of claim 16, wherein the conditions that permit amide bond formation comprise performing said amide bond formation in the presence of a peptide coupling agent.
 18. The method of claim 17, wherein the peptide coupling agent is selected from the group consisting of a chlorinating agent, a mixed anhydride, DIC, DCC, EDCI, CDI, HOBt, HOAt, pentafluorophenol, HBTU, HATU, and Mukaiyama's reagent.
 19. The method of claim 16, wherein the conditions that permit reduction comprise (a) performing said reduction in the presence of hydrogen and a Pd, Ni, Ir, Pt, Rh, Ru or Ir catalyst, (b) performing said reducing in the presence of borane or lithium aluminum hydride, or (c) a combination thereof.
 20. The method of claim 16, wherein the product of said method is cinacalcet hydrochloride. 21.-77. (canceled)
 78. A compound of formula (IV)


79. A compound of formula (VI)


80. A compound of formula (VIIB)


81. A compound of formula (XIII)

wherein R is hydrogen.
 82. A compound of formula (XVI)

wherein R is hydrogen.
 83. A compound of formula (XX) 